The genetic causes of the sequential occurrence of multiple primary malignancies in a young woman--5 years on.

The finding of three primary gynaecological malignancies in a young woman attending our unit was documented in 2001. We provide an update on this report as new events have prompted further discussion on the role of clinical guidelines in cancer management. The discovery of a genetic predisposition demonstrates the need for multidisciplinary input and heightened awareness in similar cases while the importance of treating each patient as an individual is emphasized.

Effect of B vitamins and genetics on success of in-vitro fertilisation: prospective cohort study.

BACKGROUND: There is a need to understand what affects the success of in-vitro fertilisation (IVF) and the rate of resulting twin births so that pregnancy rates can be improved and multiple gestations avoided. Our aim was to assess the role of B vitamins and genetics. METHODS: We did a prospective cohort study of 602 women undergoing fertility treatment. We assessed intake of folate and vitamin B12 with a questionnaire and measured their plasma and red-blood-cell concentrations by radioimmunoassay. We measured five B-vitamin-related gene variants in women who received treatment and in 932 women who conceived naturally. FINDINGS: The likelihood of a twin birth after IVF rose with increased concentrations of plasma folate (1.52, 1.01-2.28; p=0.032) and red-cell folate (1.28, 1.00-1.65; p=0.039). There was no association between folate and vitamin B12 levels and likelihood of a successful pregnancy. Women homozygous for the 1298 CC variant of methylenetetrahydro-folate reductase (MTHFR), rather than the AA variant, were less likely to produce a livebirth after IVF (0.24, 0.08-0.71; p=0.003) or to have had a previous pregnancy (0.42, 0.21-0.81; p=0.008). INTERPRETATION: Our findings suggest that MTHFR genotype is linked to a woman's potential to produce healthy embryos (possibly through interaction with genes related to DNA methylation). In women likely to have a successful IVF pregnancy, high folate status increases the likelihood of twin birth after multiple embryo transfer. Proposals to fortify the UK diet with folic acid could lead to an increase in the number of twins born after IVF.

Environmental risk factors for Parkinson's disease and parkinsonism: the Geoparkinson study.

OBJECTIVE: To investigate the associations between Parkinson's disease and other degenerative parkinsonian syndromes and environmental factors in five European countries. METHODS: A case-control study of 959 prevalent cases of parkinsonism (767 with Parkinson's disease) and 1989 controls in Scotland, Italy, Sweden, Romania and Malta was carried out. Cases were defined using the United Kingdom Parkinson's Disease Society Brain Bank criteria, and those with drug-induced or vascular parkinsonism or dementia were excluded. Subjects completed an interviewer-administered questionnaire about lifetime occupational and hobby exposure to solvents, pesticides, iron, copper and manganese. Lifetime and average annual exposures were estimated blind to disease status using a job-exposure matrix modified by subjective exposure modelling. Results were analysed using multiple logistic regression, adjusting for age, sex, country, tobacco use, ever knocked unconscious and family history of Parkinson's disease. RESULTS: Adjusted logistic regression analyses showed significantly increased odds ratios for Parkinson's disease/parkinsonism with an exposure-response relationship for pesticides (low vs no exposure, odds ratio (OR) = 1.13, 95% CI 0.82 to 1.57, high vs no exposure, OR = 1.41, 95% CI 1.06 to 1.88) and ever knocked unconscious (once vs never, OR = 1.35, 95% CI 1.09 to 1.68, more than once vs never, OR = 2.53, 95% CI 1.78 to 3.59). Hypnotic, anxiolytic or antidepressant drug use for more than 1 year and a family history of Parkinson's disease showed significantly increased odds ratios. Tobacco use was protective (OR = 0.50, 95% CI 0.42 to 0.60). Analyses confined to subjects with Parkinson's disease gave similar results. CONCLUSIONS: The association of pesticide exposure with Parkinson's disease suggests a causative role. Repeated traumatic loss of consciousness is associated with increased risk.

Gene-environment interactions in parkinsonism and Parkinson's disease: the Geoparkinson study.

OBJECTIVES: To investigate associations of Parkinson's disease (PD) and parkinsonian syndromes with polymorphic genes that influence metabolism of either foreign chemical substances or dopamine and to seek evidence of gene-environment interaction effects that modify risk. METHODS: A case-control study of 959 prevalent cases of parkinsonism (767 with PD) and 1989 controls across five European centres. Occupational hygienists estimated the average annual intensity of exposure to solvents, pesticides and metals, (iron, copper, manganese), blind to disease status. CYP2D6, PON1, GSTM1, GSTT1, GSTM3, GSTP1, NQO1, CYP1B1, MAO-A, MAO-B, SOD 2, EPHX, DAT1, DRD2 and NAT2 were genotyped. Results were analysed using multiple logistic regression adjusting for key confounders. RESULTS: There was a modest but significant association between MAO-A polymorphism in males and disease risk (G vs T, OR 1.30, 95% CI 1.02 to 1.66, adjusted). The majority of gene-environment analyses did not show significant interaction effects. There were possible interaction effects between GSTM1 null genotype and solvent exposure (which were stronger when limited to PD cases only). CONCLUSIONS: Many small studies have reported associations between genetic polymorphisms and PD. Fewer have examined gene-environment interactions. This large study was sufficiently powered to examine these aspects. GSTM1 null subjects heavily exposed to solvents appear to be at increased risk of PD. There was insufficient evidence that the other gene-environment combinations investigated modified disease risk, suggesting they contribute little to the burden of PD.

Multifactorial analysis of differences between sporadic breast cancers and cancers involving BRCA1 and BRCA2 mutations.

BACKGROUND: We have previously demonstrated that breast cancers associated with inherited BRCA1 and BRCA2 gene mutations differ from each other in their histopathologic appearances and that each of these types differs from breast cancers in patients unselected for family history (i.e., sporadic cancers). We have now conducted a more detailed examination of cytologic and architectural features of these tumors. METHODS: Specimens of tumor tissue (5-microm-thick sections) were examined independently by two pathologists, who were unaware of the case or control subject status, for the presence of cell mitosis, lymphocytic infiltration, continuous pushing margins, and solid sheets of cancer cells; cell nuclei, cell nucleoli, cell necrosis, and cell borders were also evaluated. The resulting data were combined with previously available information on tumor type and tumor grade and further evaluated by multifactorial analysis. All statistical tests are two-sided. RESULTS: Cancers associated with BRCA1 mutations exhibited higher mitotic counts (P = .001), a greater proportion of the tumor with a continuous pushing margin (P<.0001), and more lymphocytic infiltration (P = .002) than sporadic (i.e., control) cancers. Cancers associated with BRCA2 mutations exhibited a higher score for tubule formation (fewer tubules) (P = .0002), a higher proportion of the tumor perimeter with a continuous pushing margin (P<.0001), and a lower mitotic count (P = .003) than control cancers. CONCLUSIONS: Our study has identified key features of the histologic phenotypes of breast cancers in carriers of mutant BRCA1 and BRCA2 genes. This information may improve the classification of breast cancers in individuals with a family history of the disease and may ultimately aid in the clinical management of patients.

Comparative genomic hybridization analysis of chromosomal alterations induced by the development of resistance to thymidylate synthase inhibitors.

Acquired resistance to chemotherapy is a major obstacle to the successful treatment of cancer. In the past, technical limitations prevented the detection of genetic alterations associated with such resistance on a genome-wide scale. This study evaluated comparative genomic hybridization (CGH) as a tool to detect candidate regions of the genome associated with chemoresistance. Using a variation of conventional CGH, DNA from cell lines that were resistant to thymidylate synthase inhibitors (raltitrexed and 5-fluorouracil) and their sensitive parent cells were evaluated. In MCF-7 and H630 cells that were resistant to raltitrexed, only a single region of change (18p gain) was apparent. The third cell line, H630R10, which was resistant to 5-fluorouracil, had changes in several genomic regions following the acquisition of resistance, including 18p gain. Gain in the chromosomal region containing the thymidylate synthase gene (18p11.32) was detected by CGH in all three resistant cell lines. However, additional novel regions of interest were identified in the cells that were resistant to 5-fluorouracil. These results suggest that CGH is of potential use in the detection of regions of the genome involved in chemoresistance.

p53 mutation is a common genetic event in ovarian carcinoma.

Using the single-strand conformational polymorphism technique, we have screened 66 malignant ovarian tumors for p53 mutation in exons 5 to 8. Thirty-four of the tumors demonstrated a single-strand conformational polymorphism band shift in this region of the gene, including 6 in exon 5, 7 in exon 6, 12 in exon 7, and 10 in exon 8 (one of the tumors showed a shift for exons 7 and 8). All of the single-strand conformational polymorphism shifts have been further characterized by DNA sequencing, and 31 of 35 have been shown to represent genuine DNA alterations. These include 27 point mutations (23 missense, 2 nonsense, and 2 silent mutations), 3 deletions (a 2-base pair deletion introducing, by frameshift, a stop codon further downstream; a 3-base pair deletion; and an unusual 6-base pair deletion made up of separate 2-base pair and 4-base pair deletions), and a 4-base pair insertion (introducing a stop codon downstream). In total, 29 of the 66 (44%) carcinomas analyzed had mutations affecting the primary sequence of the p53 protein. p53 mutation was found in tumors of all International Federation of Gynecologists and Obstetricians stages, suggesting that it might be an earlier genetic event in the progression of epithelial ovarian tumors than previously thought. A significantly greater number of p53 mutations were seen in high-grade serous carcinomas than in those of endometrioid and mucinous types (0.02 > P > 0.01). Analysis of the distribution of point mutations showed no preference for any particular mutation type.

Early loss of heterozygosity on 17q in ovarian cancer. The Abe Ovarian Cancer Genetics Group.

We have studied 146 ovarian tumours (94 carcinomas, 22 tumours of low malignant potential and 30 benign tumours) for evidence of allele loss on chromosome 17p and 17q sufficient to imply the proximity of a tumour-suppressor gene. We have examined two polymorphic loci (YNZ22.2 and BHP53) on 17p13 and one on chromosome 17q (17q23-qter). Loss of heterozygosity (LOH) was detected in 34/63 (54%) informative malignant tumours at YNZ22.2 and 22/47 (47%) at BHP53; on 17q, 45/64 (70%) had LOH. Allele loss was detected in a small number of benign and borderline tumours. There was a statistically significant difference between the patterns of allele loss in serous and endometrioid groups of tumours, and allele loss occurred with significantly greater frequency on 17q than on 17p. Comparison of all malignant tumours presenting with either localized (FIGO stage I/II) or widespread (FIGO stage III/IV) disease showed that, particularly on 17q, allele loss increases in the more advanced stages. The p53 tumour-suppressor gene is implicated in ovarian carcinogenesis, and our findings suggest that an important tumour-suppressor gene may be located in the region 17q23-qter. Loss of function in this gene may be responsible for the frequently observed rapid progression of serous-type adenocarcinomas to an advanced stage.

Improving the referral process for familial breast cancer genetic counselling: findings of three randomised controlled trials of two interventions.

OBJECTIVES: To evaluate the effectiveness and cost-effectiveness of two complementary interventions, using familial breast cancer as a model condition. The primary care intervention consisted of providing computerised referral guidelines and related education to GPs. The nurse counsellor intervention evaluated genetic nurses as substitutes for specialist geneticists in the initial assessment and management of referred patients. DESIGN: The computerised referral guidelines study was a pragmatic, cluster randomised controlled trial (RCT) with general practices randomised to intervention or control groups. The nurse counsellor intervention was tested in two concurrent RCTs conducted in separate UK health service locations, using predetermined definitions of equivalence. SETTING: The computerised referral guidelines trial took place in general practices in Scotland from November 2000 to June 2001. The nurse counsellor intervention took place in a regional genetics clinic in Scotland, and in two health authorities in Wales served by a single genetics service during 2001. PARTICIPANTS: The computerised referral guidelines study involved GPs and referred patients. Both nurse counsellor intervention trials included women referred for the first time, aged 18 years or over and whose main concern was family history of breast cancer. INTERVENTIONS: The software system was developed with GPs, presenting cancer genetic referral guidelines in a checklist approach. Intervention GPs were invited to postgraduate update education sessions, and both intervention and control practices received paper-based guidelines. The intervention period was November 2000 to June 2001. For the nurse counsellor trial, trial 1 ran outpatient sessions with the same appointment length as the standard service offered by geneticists, but the nurse counsellor saw new patients at the first appointment and referred back to the GP or on to a clinical geneticist according to locally developed protocol, under the supervision of a consultant geneticist. The control intervention was the current service, which comprised an initial and a follow-up appointment with a clinical geneticist. In trial 2, a nurse counsellor ran outpatient sessions with the same appointment length as the new consultant-based cancer genetics service and new patients were seen at the first appointment and referred as in trial 1. The control intervention was a new service, and comprised collection of family history by telephone followed by a consultation with a clinical assistant or a specialist registrar, supervised by a consultant. The intervention was implemented between 1998 and 2001. MAIN OUTCOME MEASURES: In the software system trial, the primary outcome was GPs' confidence in their management of patients with concerns about family history of breast cancer. For the nurse counsellor trial, the primary outcome was patient anxiety, measured using standard scales. RESULTS: In the software system trial, 57 practices (230 GPs) were randomised to the intervention group and 29 (116 GPs) to the control group. No statistically significant differences were detected in GPs' confidence or any other outcomes. Fewer than half of the intervention GPs were aware of the software, and only 22 reported using it in practice. The estimated total cost was GBP3.12 per CD-ROM distributed (2001 prices). For the two arms of the nurse counsellor trial, 289 patients (193 intervention, 96 control) and 297 patients (197 intervention and 100 control) consented, were randomised, returned a baseline questionnaire and attended the clinic for trials 1 and 2 respectively. The analysis in both cases suggested equivalence in all anxiety scores, and no statistically significant differences were detected in other outcomes in either trial. A cost-minimisation analysis suggested that the cost per counselling episode was GBP10.23 lower in intervention arm than in the control arm and GBP10.89 higher in the intervention arm than in the control arm (2001 prices) for trials 1 and 2, respectively. Taking the trials together, the costs were sensitive to the grades of doctors and the time spent in consultant supervision of the nurse counsellor, but they were only slightly affected by the grade of nurse counsellor, the selected discount rate and the lifespan of equipment. CONCLUSIONS: Computer-based systems in the primary care intervention cannot be recommended for widespread use without further evaluation and testing in real practice settings. Genetic nurse counsellors may be a cost-effective alternative to assessment by doctors. This trial does not provide definitive evidence that the general policy of employing genetics nurse counsellors is sound, as it was based on only three individuals. Future evaluations of computer-based decision support systems for primary care must first address their efficacy under ideal conditions, identify barriers to the use of such systems in practice, and provide evidence of the impact of the policy of such systems in routine practice. The nurse counsellor trial should be replicated in other settings to provide reassurance of the generalisability of the intervention and other models of nurse-based assessment, such as in outreach clinics, should be developed and evaluated. The design of future evaluations of professional substitution should also address issues such as the effect of different levels of training and experience of nurse counsellors, and learning effects.

The pathology of familial breast cancer: histological features of cancers in families not attributable to mutations in BRCA1 or BRCA2.

Breast cancers arising in carriers of mutations in the breast cancer susceptibility genes, BRCA1 and BRCA2, differ histologically from each other and from breast cancers unselected for a family history. However, a substantial proportion of families with multiple cases of breast cancer is not attributable to these two genes (non-BRCA1/2 families). We have now characterized the pathology of 82 breast cancers from non-BRCA1/2 families. Breast cancers in non-BRCA1/2 families were of lower grade (P = 0.0018), showed fewer mitoses (P < 0.0001), less nuclear pleomorphism (P = 0.0014), less lymphocytic infiltrate (P < 0.0001), a lesser extent of the tumor with a continuous pushing margin (P = 0.004), a lesser extent of the tumor composed of solid sheets of cells (P = 0.0047), less necrosis (P = 0.002), and wereparison with BRCA2 tumors, non-BRCA1/2 tumors were lower grade (P = 0.017) and exhibited less pleomorphism (P = 0.01) and more tubule formation (P = 0.05). In comparison with control breast cancers unselected for a family history of the disease, non-BRCA1/2 tumors were of significantly lower grade (P = 0.001), showed less pleomorphism (P = 0.0002), and had a lower mitotic count (P = 0.003). The results indicate that non-BRCA1/2 breast cancers differ histologically from both BRCA1 and BRCA2 breast cancers and are overall of lower grade. They also suggest that non-BRCA1/2 breast cancers differ from nonfamilial breast cancers, but these differences may be attributable to various types of bias.

Aortic blood velocity measurement in healthy adults using a simple ultrasound technique.

The normal range of aortic blood velocity has been established in 140 healthy adults using the non-invasive technique of transcutaneous aortovelography (TAV). Velocity is independent of sex, body surface area and blood pressure but declines progressively with age so that at age 70 the mean value of peak velocity is 55% of that at age 20. Integration of the area under the velocity time curve gives an indication of stroke volume and cardiac output. These indices also decrease with age as does acceleration which may reflect left ventricular function. Measurement of aortic blood velocity and its derivatives is a safe, simple and physiologically meaningful way of assessing cardiac output and function.

Paget's disease of bone: evidence for a susceptibility locus on chromosome 18q and for genetic heterogeneity.

Paget's disease of bone is a common condition characterized by bone pain, deformity, pathological fracture, and an increased incidence of osteosarcoma. Genetic factors play a role in the pathogenesis of Paget's disease but the molecular basis of the disease remains unclear. Previous genetic linkage studies have mapped the rare Paget's disease-like bone dysplasia familial expansile osteolysis (FEO) to chromosome 18q21-22, and recent work has shown evidence of linkage between this locus and Paget's disease in one family. Here we studied the relationship between the 18q21-22 locus and Paget's disease in eight large multiplex families from diverse ethnic backgrounds with inherited Paget's disease. Paget's disease was inherited as an autosomal dominant trait in all families, with high penetrance by the sixth decade. Analysis of seven highly polymorphic markers from chromosome 18q21-22 showed positive summated two-point log10 odds ratio (lodscores) of +2.97 with the marker D18S42 at a recombination fraction (theta) = 0.05, and of +2.95 with the marker D18S60 at theta = 0.00, values which are close to the cut-off of +3.0, which is generally accepted as evidence of linkage. Segregation analysis of the haplotypes and formal statistical analysis using the HOMOG program provided evidence for genetic heterogeneity, however, with evidence for linkage in five families and against linkage in the remaining three families (chi square 8.82; df = 2; p < 0.025). Multipoint linkage analysis in the five linked families showed lodscores of above +3.5 across the whole susceptibility region and a maximum summated lodscore of 3.89 at the marker D18S465. In the three nonlinked families, negative multipoint results were obtained for the whole region, with lodscores below -2.0 in one family, excluding this as a candidate locus for the disease. Our studies demonstrate the importance of hereditary factors in the pathogenesis of Paget's disease and confirm evidence of linkage between Paget's disease and chromosome 18q21-22 in some families. This raises the possibility that Paget's disease and FEO may share a common molecular basis, perhaps due to different mutations in the same gene or family of genes. Data from three families did not support evidence of linkage to 18q21-22 however, indicating that Paget's disease is genetically heterogeneous and suggests the presence of at least one additional locus which remains to be discovered.

Human fetal testis: second trimester proliferative and steroidogenic capacities.

The period of Leydig cell hyperplasia (14-18 weeks gestation) in human fetal testis is crucial for normal gonad development. We have studied the spatio-temporal distribution of key developmental and functional markers in human fetal testis between 13-19 weeks gestation. Proliferating cell nuclear antigen-positive cells were immunolocalized to both interstitium and tubules. Image analysis confirmed an increase in positive interstitial cells during Leydig cell hyperplasia (P: < 0.05). c-Myc was localized to the interstitium with no gestational changes. The steroidogenic enzymes 3beta-hydroxysteroid dehydrogenase (protein) and cytochrome P450 17alpha-hydroxylase/C(17-20)-lyase (P450c17; messenger ribonucleic acid and protein) were confined to the Leydig cells. The number of immunopositive cells increased between 13 and 19 weeks (P: < 0.001). P450c17 mRNA (in situ hybridization) and protein were localized to the same population of interstitial Leydig cells. Androgen receptor and Bcl-2 protein (anti-apoptotic) were gradually restricted to the peritubular myoid cells as gestation progressed. Conversely, Bax protein (pro-apoptotic) was predominantly localized to the tubule Sertoli cells, whereas the germ cells were Bax immunonegative. In conclusion, human fetal Leydig cell hyperplasia is characterized by increasing numbers of proliferating cells and increased expression of steroidogenic enzymes. The Bcl-2-positive, Bax-negative status of the peritubular myoid cells may be a strategy for cell survival.

Rapid diagnosis and identification of cross-over sites in patients with glucocorticoid remediable aldosteronism.

Glucocorticoid remediable aldosteronism (GRA) is an autosomal dominant cause of primary aldosteronism and high blood pressure resulting from a chimeric 11beta-hydroxylase/aldosterone synthase gene. Abnormal expression of aldosterone synthase causes primary aldosteronism, which can be inhibited by glucocorticoids. Diagnosis of GRA has depended on the identification of a restriction enzyme product in genomic DNA of affected individuals. Recently, a two-tube long PCR method was described that allowed diagnosis of GRA in a kindred in Australia. A similar long PCR method confirmed the diagnosis of GRA in members of five northeastern Scotland families previously identified by Southern blotting and detected affected members of five GRA families previously identified in Glasgow. A multiplex PCR protocol is described here that allows the control aldosterone synthase amplification and chimeric gene amplification to be carried out in the same tube. We describe the regions of cross-over in each of 10 kindreds identified in Scotland. To identify cross-over regions in each of the kindreds, the chimeric long PCR product was cloned and sequenced. Five cross-over sites were identified ranging from intron 2 to exon 4, indicating the reliability of the method in identifying chimeric genes resulting from different sites of cross-over.

Non-penetrance in a MODY 3 family with a mutation in the hepatic nuclear factor 1alpha gene: implications for predictive testing.

The most common cause of maturity-onset diabetes of the young (MODY) is a mutation in the hepatic nuclear factor 1alpha (HNF1alpha) gene (MODY3). We describe a family in which a missense mutation causing a Thr-Ile substitution at codon 620 has been found in all affected members. The mutation is not fully penetrant as two family members aged 87 and 46 have the mutation but do not have diabetes. The severity and age of diagnosis of diabetes varies widely within the family, and most presented over the age of 25. HNF1alpha mutation screening should be considered in any family with autosomal dominant inheritance of diabetes where one member has presented with diabetes before the age of 25. Predictive testing is now possible within the majority of MODY families, and is of clinical benefit, but the possibility of non-penetrance should be addressed during counselling and interpretation of results.

Teaching undergraduates about familial breast cancer: comparison of a computer assisted learning (CAL) package with a traditional tutorial approach.

We have developed a computer assisted learning package for teaching clinical medical students about familial breast cancer. It explains the principles of genetic predisposition to breast cancer, the association with other cancers, the principles of family history taking and confirmation, risk assessment and possible interventions. Clinical medical students were randomised to either conventional teaching or CAL, 48 students attended the evaluation session. Students randomised to conventional teaching received a 20 min mini-lecture, those randomised to CAL completed the package with technical, but not academic support available. At the end of the intervention both groups of students completed a short written assessment of acceptability and knowledge and understanding of breast cancer genetics. There was no significant difference between the CAL and mini-lecture groups in terms of marks or acceptability. Thus CAL appears to be an acceptable and effective method of teaching clinical medical students about familial breast cancer. Although time consuming to develop, CAL can be used in a variety of settings to increase curriculum flexibility. Methods of motivating students to complete the CAL, and of providing educational support are being explored.

Epidermal growth factor (EGF) increases the in vitro invasion, motility and adhesion interactions of the primary renal carcinoma cell line, A704.

Metastasis is a multistep process that involves alterations in a tumour cell's invasion, motility and adhesive capabilities. This study examined the effect of EGF on the in vitro invasion, motility and adhesion of the primary renal adenocarcinoma cell line, A704. Stimulation of the tumour cells by EGF (40 ng/ml) for a period of 24 h increased the in vitro invasion (P = 0.040) and motility (P = 0.039). Cell adhesion was examined on fibronectin, laminin, collagen IV and a 1:1:1 mix of the three extracellular matrix components. After EGF (40 ng/ml) stimulation, adhesion was significantly decreased on fibronectin (P = 0.022) and collagen type IV (P = 0.026), but increased on the 1:1:1 mix of extracellular matrix components (P = 0.022). The 92 kDa matrix metalloproteinase (MMP-9) present in the cell-conditioned medium was also increased after a 24 h stimulation with EGF (40 ng/ml) when measured. Hence, EGF can modulate the in vitro invasion, motility, adhesiveness and matrix metalloproteinase production in the A704 cell line, and subsequently may have a role in the metastatic potential of some renal carcinomas.

Polymorphisms in P21CIP1/WAF1 are not correlated with TP53 status in sporadic ovarian tumours.

In breast cancers and sarcomas, a variant polymorphism in the cell cycle inhibitor P21CIP1/WAF1 is under-represented in those individuals whose tumours contain mutated TP53. The aim of this study was to determine whether this variant polymorphism was also under-represented in those with ovarian carcinoma and TP53 mutations. We studied lymphocyte DNA from 104 women with ovarian carcinoma, 15 with borderline tumours and 16 with benign tumours, using a previously-reported PCR-RFLP technique. 96 of the ovarian carcinoma cases had been previously examined for mutations in TP53 and/or for overexpression of the TP53 protein. The variant allele was seen in 11 out of 104 women (10.6%) with ovarian carcinoma. There was no significant difference in the distribution of the variant allele in the women whose tumours had (7/47) or did not have (4/49) TP53 mutations (P = 0.523). It does not appear that the presence of this variant allele of P21CIP1/WAF1 has any aetiological role in ovarian carcinomas. Studies in other tumours support this finding.

Current policies for surveillance and management in women at risk of breast and ovarian cancer: a survey among 16 European family cancer clinics. European Familial Breast Cancer Collaborative Group.

The recent isolation of breast cancer predisposing genes (BRCA1 and BRCA2) allows the identification of carriers within affected families. These carriers have a 50-85% risk of developing breast or ovarian cancer and need careful follow-up. The purpose of this study was to evaluate the management and screening protocols implemented in high risk families at various family cancer clinics in Europe. A questionnaire was mailed to the members of the European Familial Breast Cancer Collaborative Group (n = 30) requesting information on the following issues: indication for surveillance of breasts and ovaries, the recommended protocol, coordination of the screening examination, prophylactic surgery, the specific management of breast cancer in a mutation carrier and the use of oestrogen. 16 centres from nine countries responded. Most centres recommend surveillance of the breasts if the lifetime risk exceeds 15-20%. The surveillance protocol that is generally advised comprises monthly self breast examination, examination by a specialist every 6 months and annual mammography, all starting from an age between 25 and 35 years. Surveillance of the ovaries is recommended in BRCA1 and BRCA2-mutation carriers, in members from breast/ovarian cancer families and in some centres in 'breast cancer only' families with an early onset of breast cancer. The recommended protocol includes gynaecological examination, sonography and estimation of CA-125 at yearly intervals starting from the age 30-35 years. Prophylactic mastectomy is considered for proven mutation carriers in some centres. Most centres consider prophylactic oophorectomy in mutation carriers and some centres also consider it for members of breast/ovarian cancer families. This survey provides insight into the guidelines for surveillance and management of familial breast cancer used at various family cancer clinics in Europe; this insight may contribute to the appropriate management of these high risk women. It should be emphasised that most recommendations are based on experts' opinion rather than on any specific studies.

Prothrombotic genotypes are not associated with pre-eclampsia and gestational hypertension: results from a large population-based study and systematic review.

DNA samples collected as part of a large population-based case-control study were genotyped to examine the associations of five prothrombotic gene polymorphisms with pre-eclampsia (PE) and gestational hypertension (GH). The polymorphisms studied were: G1691A in Factor V (Factor V Leiden; FVL), prothrombin G20210A, methylenetetrahydrofolate reductase (MTHFR) C677T, plasminogen activator inhibitor-1 4G/5G and the platelet collagen receptor alpha2beta1 C807T. A group of 404 women who developed PE were retrospectively compared with 303 women with GH and 164 control women. The frequency of genotypes did not differ significantly between cases of PE or GH and controls for any of the five polymorphisms studied. We conclude that these prothrombotic genotypes are not associated with the development of PE or GH in our population. The systematic review supports our conclusion, for all but cases of severe disease. which appear to be associated with FVL and, to a lesser extent, MTHFR C677T. There is little value in antenatal screening for prothrombotic polymorphisms to predict the development of pre-eclampsia or gestational hypertension.